The rupture of the fibrous cap is the critical event leading to thromboembolic complications on the luminal surface of advanced atherosclerotic plaques. The factors that set the stage for plaque disruption include progressive cap atrophy with loss of cells and matrix. Unfortunately, these beliefs are hard to test because of a lack of animal models. We propose to solve this problem by an interdisciplinary approach combining human tissue and animal model studies of molecular pathways that could underlie this process. In Grant 1 (T. Hatsukami and C. Yuan), we will study, using high resolution magnetic resonance imaging, a cohort of patients with moderate internal carotid artery stenosis. We will test the hypothesis that the fibrous caps of these lesions generally are thick and that thinning of the cap develops after the plaque enlarges and the lumen narrows. We will also determine whether ischemic neurological events or plaque rupture assessed by histological evaluation of excised plaques correlates with fibrous cap thinning. In Grant 2 (A. Clowes and M. Reidy), we will make use of animal models to define the contribution of increased apoptosis and matrix metalloproteinase expression to fibrous cap atrophy. We will attempt to demonstrate in rats that luminal narrowing by a rigid wrap models the state of an advanced human atherosclerotic internal carotid artery and causes cell death and intimal matrix degradation, a process that might depend upon certain secondary stress signaling pathways. In Grant 3 (S.M. Schwartz and D. Dichek), we will define the protease cascade leading to cell death in human lesions and correlate these findings in operative specimens with MR evidence of cap thinning. We will also test the hypothesis that certain fibrous caps do not rupture because of increased expression of anti-apoptotic genes. Finally, we will attempt to diminish or enhance the stability of fibrous caps in apo E deficient mice by gene transfer of select pro-or anti-apoptotic genes. These collaborative studies should provide novel insights into the basic mechanisms underlying fibrous cap atrophy and disruption.